Apoptosis is closely involved in morphogenesis and histogenesis in the development process, maintenance of homeostasis, and bio-defense, and it is cell death having an important role in maintaining individual lives. When the death process regulated by genes is congenitally or postnatally hindered, apoptosis is excessively induced or inhibited to cause functional disorders in various organs, and thus diseases (Saishin Igaku, vol. 54, p. 825, 1999).
Lately, it has been come out that apoptosis plays an important role in occurrence or development of several diseases (The New England Journal of Medicine, vol. 341, p. 759, 1999). In a mammalian heart, it is considered that heart muscle cells are finally differentiated cells, and lose proliferation activity. Accordingly, when heart muscle cells disappear by apoptosis, the heart contraction should be maintained only by remaining cells. Disappearance of heart muscle cells beyond threshold necessary for maintaining the heart contraction would result in abnormal heart functions and diseases. Apoptosis of heart muscle cells is actually observed in various animal models with cardiac insufficiency or in human patients with cardiac insufficiency, and it is noted that disappearance or lack of heart muscle cells by apoptosis may be involved in onset and progress of cardiac insufficiency (The New England Journal of Medicine, vol. 335, p. 1182, 1996). It is further recognized that in heart muscle cells of human patients with cardiac insufficiency, an apoptosis-inhibitory factor Bcl-2 is expressed in excess, which is a possible compensation mechanism for cardiac insufficiency (The New England Journal of Medicine, vol. 336, p. 1131, 1997); that serum levels of soluble Fas (sFas has an inhibitory activity on apoptosis) which lacks a membrane penetration domain in the Fas receptor known as an apoptosis inducing receptor, are increased significantly in proportion to severeness in NYHA class (New York Heart Association Functional Class) but independently of fundamental diseases, and thus an increase in serum levels of sFas is considered to be a compensatory mechanism to inhibit promotion of apoptosis in cardiac insufficiency (Journal of the American College of Cardiology, vol. 29, p. 1214, 1997); and that in the heart with congestive cardiomyopathy, deoxyribonuclease I (DNase I) considered as a indicator of apoptosis is increased 7-fold or more than in healthy persons (Journal of Molecular & Cell Cardiology, vol. 28, p. 95, 1996).
When considered at the level of internal organs, the functions of the heart muscle are lowered in human cardiac diseases, and insufficient heart muscle contraction often endangers the maintenance of the life. Abnormalities, for example, myocardial disorders, abnormal heart pumping, pressure burden due to high blood pressure, volume burden due to acute nephritis, and insufficient blood pumping caused by these abnormalities lead to the onset of cardiac insufficiency. Against these abnormalities, the sympathetic nervous system, the internal secretion system, and the like work together to start a compensating mechanism, resulting in cardiac hypertrophy accompanied by hypertrophy of myocardial cells. However, when these abnormalities occur alone or in combination persistently and chronically, the hypertrophied myocardial cells are not sufficiently supplied with blood, and thus the myocardial cells disappear due to apoptosis, etc. As a result, the compensating mechanism fails to work, leading to a cardiac insufficiency syndrome accompanied by myocardial disorders such as insufficient heart contraction, a reduction in pumped blood, circulatory disorders in internal organs, venostasis, and body fluid retention.
At present, the cardiac insufficiency syndrome is treated by using cardiotonic glycosides such as digoxin, sympathetic agents such as dobutamine, phosphodiesterase inhibitors such as amrinone, vasodilators such as hydralazine, calcium antagonist, angiotensin converting enzyme inhibitor and angiotensin receptor antagonist, and dilated cardiomyopathy is treated by β-blockers, etc.
On the other hand, 1,3-benzothiazinone compound whose 2-position is substituted by pyridyl is described in Chemical Abstract 51:17927g, however, the activity thereof is not described on it.
Furthermore, 1,3-benzothiazinone compound having heart muscle cells apoptosis inhibitory effect are disclosed on WO 02/18356, which is an earlier application of this applicant.
The drugs for treating cardiac insufficiency syndrome don't possess efficient effect. Therefore the excellent drug for preventing and/or treating cardiac insufficiency syndrome is desired.